Novel vitamin D analogs

ABSTRACT

Novel vitamin D analogs, markedly active in the fields of cell proliferation and differentiation, are selected from among (4E,6E)-7-{3-[2-(3,4-bis-hydroxymethylphenyl)-ethyl] phenyl}-3-ethylnona-4, 6-dien-3-ol, (E)-6-[3-(3,4-bis-hydroxymethylbenzyloxy)phenyl]1,1,1-trifluoro-2-trifluoromethyloct-5-en-3-yn-2-ol, (3E,5E)-6-[3-(3 ,4-bis-hydro xymethylbenzyloxy)-phenyl]-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol, (E)-6-{3-[2-(3,4-bis-hydroxymethylphenyl)ethyl]phenyl }-1,1,1-trifluoro-2-trifluoromethyloct-5-en-3-yn-2-ol, and (3E,5E)-6-{3-[2-(3,4-bis-hydroxymethylphenyl)-ethyl] phenyl-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol, and the geometric isomers thereof and these compounds in which one or more of the hydroxyl functions are protected by a protective group —(C═O)—R, in which R is a linear or branched alkyl radical having from 1 to 6 carbon atoms, an aryl radical having from 6 to 10 carbon atoms, or an aralkyl radical having from 7 to 11 carbon atoms, the aryl radical or the aralkyl radical optionally being mono- or disubstituted by a hydroxy group, an alkoxy radical having from 1 to 3 carbon atoms, a halogen atom, a nitro function or by an amino function, and mixtures thereof.

CROSS-REFERENCE TO PRIORITY/PCT APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119 ofFR-01/06731, filed May 22, 2001, and is a continuation of PCT/FR02/01726, filed May 22, 2002 and designating the United States(published in the French language on Nov. 28, 2002 as WO 02/094754 A1;the title and abstract were also published in English), both herebyexpressly incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] 1. Technical Field of the Invention

[0003] The invention relates, by way of novel and useful industrialproducts, to biaromatic compounds which are vitamin D analogs.

[0004] The invention likewise relates to the process for theirpreparation and their utilization in pharmaceutical compositionsintended for use in human or veterinary medicine, or else furthermore incosmetic compositions.

[0005] The compounds according to the invention have a marked activityin the fields of cell proliferation and differentiation and areadministered more particularly for the topical and systemic treatment ofdermatological complaints, conditions or afflictions (or others) linkedto a keratinization disorder, complaints, conditions or afflictionshaving an inflammatory and/or immunoallergic component and ofhyperproliferation of tissues of ectodermal origin (skin, epithelium . .. ), whether benign or malignant. These compounds can in addition beused to combat aging of the skin, whether photoinduced or chronologicaland to treat cicatrization disorders.

[0006] It is likewise possible to use the compounds according to theinvention in cosmetic compositions for body and hair hygiene.

[0007] 2. Description of Background/Related/Prior Art

[0008] Vitamin D is a vitamin essential for the prevention and treatmentof defects of cartilage mineralization (rachitis) and of bone(osteomalacia), and even of certain forms of osteoporosis in elderlysubjects. However, it is now known that its functions extend even beyondthe regulation of bone metabolism and of calcium homeostasis. Amongthese can be mentioned its actions on proliferation and on celldifferentiation and the control of immune defenses. Their discovery hasopened the way to novel therapeutic approaches in dermatology,cancerology, as well as in the field of autoimmune illnesses and that oforgan or tissue transplantation.

[0009] An efficacious therapeutic contribution has long been knownagainst the toxicity of this vitamin (sometimes fatal hypercalcemia).Currently, structural analogs of vitamin D are being synthesized, someof which only retain the differentiating properties and do not have anyaction on the calcium metabolism.

[0010] The assignee hereof has already proposed in WO 00/26167 (D1)novel compounds which are vitamin D analogs which show a selectiveactivity on cell proliferation and differentiation without havinghypercalcemic character. These compounds which are vitamin D analogs arein particular more easily synthesizable and therefore more economic withrespect to what was known previously.

SUMMARY OF THE INVENTION

[0011] It has now surprisingly and unexpectedly been determined thatcertain compounds not specifically described in WO 00/26167 (D1) butconfirming the general formula described elicit a biological activityvery superior to that of the compounds specifically described. Thisactivity is so strong that it approaches the activity of natural vitaminD.

[0012] Thus, the present invention relates to at least one compoundselected from among the following compounds:

[0013](4E,6E)-7-{3-[2-(3,4-bis-hydroxymethylphenyl)-ethyl]phenyl}-3-ethylnona-4,6-dien-3-ol;

[0014] (E)-6-[3-(3,4-bis-hydroxymethylbenzyloxy)phenyl]-1, 1,1-trifluoro-2-trifluoromethyloct-5-en-3-yn-2-ol;

[0015](3E,5E)-6-[3-(3,4-bis-hydroxymethylbenzyloxy)-phenyl]-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol;

[0016](E)-6-{3-[2-(3,4-bis-hydroxymethylphenyl)ethyl]-phenyl}-1,1,1-trifluoro-2-trifluoromethyloct-5-en-3-yn-2-ol;(3E,5E)-6-{3-[2-(3,4-bis-hydroxymethylphenyl)-ethyl]phenyl-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol,as well as their geometric isomers and these compounds in which one ormore of the hydroxyl functions are protected by a protective group oftype —(C═O)—R, with R representing a linear or branched alkyl radicalhaving from 1 to 6 carbon atoms, or an aryl radical having from 6 to 10carbon atoms, or an aralkyl radical having from 7 to 11 carbon atoms,the aryl radical or the aralkyl radical being able to be mono- ordisubstituted by a hydroxy group, by an alkoxy group having from 1 to 3carbon atoms, by a halogen atom, by a nitro function or by an aminofunction, and their mixtures.

[0017] Linear or branched alkyl radical having from 1 to 6 carbon atomsis understood as preferably meaning a methyl, ethyl, isopropyl,tert-butyl or hexyl radical.

[0018] Aryl radical having from 6 to 10 carbon atoms is understood asmeaning a phenyl or naphthyl radical.

[0019] Aralkyl radical having from 7 to 11 carbon atoms is understood asmeaning a benzyl or methylnaphthyl radical.

[0020] Halogen atom is understood as meaning a fluorine, bromine orchlorine atom.

[0021] The present invention likewise relates to the processes forpreparation of the compounds indicated above.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

[0022] FIGS. 1 to 4 represent reaction schemes which can be employed forthe preparation of the compounds according to the invention.

[0023] Thus, the compound of example 1 can be obtained (FIG. 1) startingfrom the derivative (6) by reaction with ethyllithium at −78° C. in asolvent such as THF and then deprotection of the hydroxyl groups in thepresence of tetrabutylammonium fluoride.

[0024] The compound (6) can be obtained starting from3-bromo-propiophenone (1) by a reaction sequence comprising:

[0025] the formation of the derivative (2) by protection of the ketonefunction in dioxolane form and then the formation of the aldehydefunction starting from the corresponding lithien in the presence of DMF.

[0026] The formation of the derivative (3) by a reaction of theHomer-Emmons type between the phosphonate derivative (compound A) andthe benzaldehyde (2), then hydrogenation in the presence of palladium oncarbon.

[0027] The formation of the derivative (4) by reduction of the esterfunctions in the presence of lithium aluminum hydride, deprotection ofthe ketone in the presence of para-toluenesulfonic acid and protectionof the alcohol functions in the form of tert-butyldimethylsilyl.

[0028] The formation of the derivative (5) by a reaction of Homer-Emmonstype with triethyl phosphono-acetate and then reduction of the esterfunction in the presence of lithium aluminum hydride and oxidation ofthe alcohol function in the presence of manganese dioxide.

[0029] The formation of the derivative (6) by a reaction ofHorner-Emmons type between triethyl phosphono-acetate and the aldehydederivative (5) or directly by a reaction of Homer-Emmons type betweentriethyl phosphonocrotonate and the ketone derivative (4).

[0030] The compound A being able to be prepared starting fromtrimellitic anhydride according to the reaction scheme represented inFIG. 4.

[0031] The compounds of examples 2 and 4 can be obtained (FIGS. 2 and 3)respectively starting from the derivative (13) and from the derivation(15) by deprotection of the alcohol functions in the presence oftetrabutylammonium fluoride.

[0032] The compounds of examples 3 and 5 can be obtained (FIGS. 2 and 3)respectively starting from the derivative (13) and from thederivation(15) by reduction of the triple bond to a double bond of transconfiguration with lithium aluminum hydride in the presence of sodiummethoxide in a solvent such as THF and then deprotection of the alcoholfunctions in the presence of tetrabutylammonium fluoride.

[0033] The compound (13) being able to be obtained starting from3-hydroxypropiophenone (7) by a reaction sequence comprising:

[0034] The formation of the derivative (8) by protection of the phenolgroup in the form of tert-butyl-dimethylsilyl.

[0035] The formation of the derivative (9) by a reaction of Homer-Emmonstype with triethyl phosphono-acetate and then reduction of the esterfunction in the presence of lithium aluminum hydride and oxidation ofthe alcohol function in the presence of manganese dioxide.

[0036] The formation of the derivative (10) by a reaction of Corey-Fuchstype.

[0037] The formation of the derivative (11) by deprotection of thephenolic function and then coupling reaction with the brominatedderivative (compound B) in the presence of sodium hydride in a solventsuch as DMF.

[0038] The formation of the derivative (12) by deprotection of thebenzoate groups and then reprotection in the form oftert-butyldimethyl-silyloxy groups.

[0039] The formation of the derivative (13) by reaction withbutyllithium and then with hexafluoroacetone.

[0040] The compound B being able to be prepared starting fromtrimellitic anhydride according to the reaction scheme represented inFIG. 4.

[0041] The compound (15) being able to be obtained starting from thederivative (5) by transformation of the aldehyde function to anacetylenic function (14) according to a reaction of Corey-Fuchs type andthen lithiation with butyllithium and reaction with hexa-fluoroacetone.

[0042] The protection of the hydroxy functions takes place by acustomary method as described in the literature, for example by reactionof a corresponding acid chloride of type RCOCl in a solvent such as THFor dichloromethane in the presence of a base such as pyridine ortriethylamine.

[0043] The compounds according to the invention have biologicalproperties analogous to those of vitamin D, especially the properties oftransactivation of vitamin D response elements (VDRE), such as anagonist activity with respect to receptors of vitamin D or of itsderivatives. Vitamins D or their derivatives are understood as meaning,for example, the derivatives of vitamin D2 or D3 and in particular1,25-dihydroxy-vitamin D3 (calcitriol).

[0044] This agonist activity with respect to vitamin D receptors or itsderivatives can be demonstrated “in vitro” by methods recognized in thefield of the study of gene transcription (Hansen et al., The Society ForInvestigative Dermatologie, vol. 1, No 1, April 1996).

[0045] By way of example, the VDR agonist activity can be tested on theHeLa cell line by cotransfection of an expression vector for the humanVDR receptor and of the reporter plasmid p240Hase-CAT. The agonistactivity can be characterized in this cotransfection system by thedetermination of the dose necessary to obtain 50% of the maximumactivity of the product (AC50). The detail of the protocol of this testas well as the results obtained with the compounds according to theinvention are described in example 7 of the present application.

[0046] The biological properties analogous to vitamin D can likewise bemeasured by the capacity of the product to inhibit the proliferation ofnormal human keratinocytes (NHK in culture). The product is added to NHKcultured under conditions favoring the proliferative state. The productis left in contact with the cells for five days. The number ofproliferative cells is measured by incorporation of bromodeoxyuridine(BRdU) into the DNA. The protocol of this test as well as the resultsobtained with the compounds according to the invention are described inexample 8 of the present application.

[0047] The biological properties analogous to vitamin D can likewise bemeasured by the capacity of the product to induce the differentiation ofHL60 promyelocytic leukemia cells. The protocol of this test as well asthe results obtained with the compounds according to the invention aredescribed in example 9 of the present application.

[0048] The agonist activity on vitamin D receptors of the compounds ofthe invention can be likewise evaluated “in vivo” by induction of24-hydroxylase in SKH mice. (Voorhees et. al., 1997, 108: 513-518). Thetest protocol used as well as the results obtained with the compoundsaccording to the invention are described in example 10 of the presentapplication.

[0049] The present invention likewise relates by way of medicament tothe compounds described above.

[0050] The compounds according to the invention are particularly highlysuitable in the following fields of treatment:

[0051] dermatological complaints linked to a keratinization disorderhaving a bearing on differentiation and proliferation such as commonacne, blackheads, polymorphs, rosacea, nodulocystic acne, acneconglobata, senile acne, secondary acne such as solar, medicinal orprofessional acne;

[0052] ichthyosis, ichthyosiform states, Damier's syndrome, palmoplantarkeratodermia, leucoplasia and leucoplasiform states, cutaneous or mucous(buccal) lichen;

[0053] dermatological complaints with an inflammatory immunoallergiccomponent, with or without cell proliferation disorder, and such as allforms of psoriasis, whether it be cutaneous, mucous or ungual, and evenpsoriatic rheumatism, or else cutaneous atopy, such as eczema orrespiratory atopy or else gingival hypertrophy;

[0054] dermal or epidermal proliferations whether they are benign ormalignant, whether they are or are not of viral origin such as commonwarts, planar warts and verruciform epidermodysplasia, oral or floridpapillomatoses, T lymphoma, and proliferations being able to be inducedby ultraviolet, especially in the case of baso- and spinocellularepithelioma, as well as cutaneous precancerous lesions such askeratoacanthomas;

[0055] immune dermatoses such as lupus erythematosus, bullous immunediseases or collagen diseases, such as scleroderma;

[0056] dermatological or general complaints with an immunologicalcomponent;

[0057] sebaceous function disorders such as hyper-seborrhea of acne orsimple seborrhea;

[0058] cutaneous disorders due to exposure to UV rays, aging of theskin, whether it be photoinduced or chronological, pigmentations andactinic keratoses, or any pathologies associated with chronological oractinic aging;

[0059] cicatrization disorders or stretch marks,

[0060] inflammatory complaints such as arthritis, complaints of viralorigin at the cutaneous or general level, such as Kaposi's syndrome;

[0061] ophthalmological complaints, especially corneopathy;

[0062] cancerous or precancerous states of cancers having or being ableto be induced by vitamin D receptors, such as breast cancer, leukemia,myelodysplasic syndromes and lymphomas, carcinomas of the cells of themalpighian epithelium and gastrointestinal cancers, melanomas, andosteosarcoma;

[0063] alopecia of different origins, especially alopecia due tochemotherapy or to radiation;

[0064] immune complaints, such as autoimmune diseases, diabetes mellitusof type 1, multiple sclerosis, lupus and lupus type complaints, asthma,glomerulonephritis; selective dysfunctions of the immune system, such asAIDS, immune rejection;

[0065] endocrine complaints;

[0066] complaints characterized by an abnormal management ofintracellular calcium, pathologies in which the calcium metabolism isinvolved, such as muscular ischemia;

[0067] deficiencies in vitamin D and other complaints of the homeostasisof minerals in the plasma and the bones, such as rachitis, osteomalacia,osteoporosis, especially in the case of menopausal women, renalosteodystrophia, or complaints of the parathyroid function;

[0068] complaints of the cardiovascular system such as arteriosclerosisor hypertension as well as non-insulin-dependent diabetes.

[0069] In the therapeutic fields mentioned above, the compoundsaccording to the invention can be advantageously employed in combinationwith retinoids, with corticosteroids or estrogens, in association withantioxidants, with α-hydroxy acids, β-hydroxy acids or α-keto acids ortheir derivatives, with ion channel blockers, or else in associationwith other medicaments known to interfere with the immune system (forexample cyclosporin, FK 506, glucocorticoids, monoclonal antibodies,cytokines or growth factors . . . ).

[0070] Retinoids are understood as meaning natural or synthetic ligandsof the RAR or RXR receptors.

[0071] Antioxidants are understood as meaning, for example,α-tocopherol, superoxide dismutase, ubiquinol or certain metalchelators.

[0072] α-Hydroxy or α-keto acids or their derivatives are understood asmeaning, for example, lactic, malic, citric, glycolic, mandelic,tartaric, glyceric, ascorbic acids, as well as their salts, amides oresters.

[0073] β-Hydroxy acids or their derivatives are understood as meaning,for example, salicylic acid as well as its salts, amides or esters.

[0074] Ion channel blockers are understood as meaning, for example,potassium channel blockers, and in particular minoxidil(2,4-diamino-6-piperidino-pyrimidine 3-oxide) and its derivatives.

[0075] The present invention likewise relates to a pharmaceuticalcomposition comprising at least one compound such as defined above.

[0076] The administration of the compounds according to the inventioncan be carried out by the enteral, parenteral, topical or ocular route.

[0077] By the enteral route, the pharmaceutical compositions can bepresent in the form of tablets, of gelatine capsules, of coated tablets,of syrups, of suspensions, of solutions, of powders, of granules, ofemulsions, of microspheres or nanospheres or lipid vesicles or polymersallowing controlled release. By the parenteral route, the compositionscan be present in the form of solutions or suspensions for perfusion orfor injection. The compounds according to the invention are generallyadministered in a daily dose of approximately 0.001 μg/kg to 1,000 μg/kgand preferably of approximately 0.01 μg/kg to 100 μg/kg of body weightin 1 to 3 doses.

[0078] By the topical route, the pharmaceutical compositions based oncompounds according to the invention are intended for the treatment ofthe skin and of the mucous membranes and are present in the form ofsalves, of creams, of milks, of ointments, of powders, of moistenedswabs, of solutions, of gels, of sprays, of lotions or of suspensions.They can likewise be present in the form of microspheres or nanospheresor lipid or polymeric vesicles or polymeric patches and of hydrogelsallowing controlled release. These compositions by the topical route canbe present either in anhydrous form, or in aqueous form according to theclinical indication.

[0079] By the ocular route, these are principally eye lotions.

[0080] These compositions for the topical or ocular route contain atleast one compound according to the invention in a concentration ofpreferably between 0.0001 and 5% and preferably between 0.001% to 1%with respect to the total weight of the composition.

[0081] The compounds according to the invention are likewise used in thecosmetic field, in particular in bodily and hair hygiene and especiallyfor the treatment of skin with a tendency to acne, for the regrowth ofthe hair, prevention of hair loss, to combat the greasy aspect of theskin or of the hair, in protection against the harmful effects of thesun or in the treatment of physiologically dry skin, in order to preventand/or to combat photoinduced or chronological aging.

[0082] In the cosmetic field, the compounds according to the inventioncan be advantageously employed in combination with the retinoids, withcorticosteroids, in association with antioxidants, with α-hydroxy orα-keto acids or their derivatives, or else with ion channel blockers.

[0083] The different products combined with the compounds of the presentinvention are such as defined above.

[0084] The present invention therefore likewise aims at a cosmeticcomposition containing, in a cosmetically acceptable support, at leastone compound such as defined above. This cosmetic composition can bepresent especially in the form of a cream, of a milk, of a lotion, of agel, of microspheres or nanospheres or lipid or polymeric vesicles, of asoap or of a shampoo.

[0085] The concentration of compound according to the invention in thecosmetic compositions can be between 0.001% and 3% by weight withrespect to the total weight of the composition.

[0086] The pharmaceutical and cosmetic compositions according to theinvention can, in addition, contain inert or even pharmacodynamically orcosmetically active additives or combinations of these additives andespecially: wetting agents; depigmenting agents such as hydroquinone,azelaic acid, caffeic acid or kojic acid; emollients; hydrating agentssuch as glycerol, PEG 400, thiamorpholinone and its derivatives or urea;antiseborrheic or antiacne agents, such as S-carboxy- methylcysteine,S-benzylcysteamine, their salts and their derivatives, or benzoylperoxide; antibiotics such as erythromycin and its esters, neomycin,clindamycin and its esters, the tetracyclines; antifungal agents such asketoconazole or the polymethylene-4,5-isothiazolin-3-ones; agentsfavoring the regrowth of the hair, such as minoxidil(2,4-di-amino-6-piperidinopyrimidine 3-oxide) and its derivatives,diazoxide (7-chloro-3-methyl-1,2,4-benzo-thiadiazine 1,1-dioxide) andphenytoin (5,4-diphenyl-imidazolidine-2,4-dione); nonsteroidalanti-inflammatory agents; carotenoids and, especially, β-carotene;antipsoriatic agents such as anthralin and its derivatives and finallyeicosa-5,8,11,14-tetra-ynoic and eicosa-5,8,11-trynoic acids, theiresters and amides.

[0087] The compositions according to the invention can likewise containagents for improving the taste, preservatives such as esters ofparahydroxybenzoic acid, stabilizers, humidity regulators, pHregulators, osmotic pressure modifiers, emulsifiers, UV-A and UV-Bfilters, antioxidants, such as α-tocopherol, butylhydroxyanisole orbutylhydroxytoluene.

[0088] In order to further illustrate the present invention and theadvantages-thereof, the following specific examples are given, it beingunderstood that same are intended only as illustrative and in nowiselimitative. The examples to follow also present various actualformulations based on such compounds as well as examples of theevaluation test of the biological activity of the compounds according tothe invention.

EXAMPLE 1(4E,6E)-7-{3-[2-(3,4-Bis-hydroxymethylphenyl)ethyl]-phenyl}-3-ethylnona-4,6-dien-3-ol

[0089] (a) 2-(3-Bromophenyl)-2-ethyl[1,3]dioxolane

[0090] 15 g (70 mmol) of 3-bromopropiophenone are dissolved in 250 ml oftoluene, and 20 ml (350 mmol) of ethylene glycol are added, as well as660 mg (3.5 mmol) of paratoluenesulfonic acid. The assembly is equippedwith a Dean-Stark type water extractor, and the reaction medium andraised to reflux for 20 h. After cooling, treatment with a solution ofpotassium bicarbonate and extraction with ethyl ether, the desiredproduct is pure without purification, and obtained in the form ofyellowish oil (m=17.8 g; Y=99%).

[0091] (b) 3-(2-Ethyl[1,3]dioxolan-2-yl)benzaldehyde

[0092] 17.8 g (70 mmol) of 2-(3-bromophenyl)-2-ethyl-[1,3]dioxolane aredissolved in 300 ml of THF and the mixture is cooled to −78° C. 34 ml(85 mmol) of a 2.5 M solution of butyllithium are added slowly, and themixture is stirred for 30 minutes. 8.1 ml (105 mmol) of DMF are thenadded, and the mixture is brought back to 0° C., then treated with asaturated solution of ammonium chloride. After extraction with ethylether, the desired aldehyde is obtained in the form of yellow oil (m =14g; Y =97%).

[0093] (c) Dimethyl4-{(E)-2-[3-(2-ethyl[1,3]dioxolan-2-yl)-phenyl]vinyl)phthalate

[0094] 10.3 g (30 mmol) of dimethyl 4-(diethoxy-phosphorylmethyl)phthalate are dissolved in 100 ml of anhydrous THF, and the mixture iscooled to 0° C. 3.4 g (30 mmol) of potassium tert-butoxide are added inportions, and the mixture is stirred for 30 minutes. A solution of 5.6 g(27.3 mmol) of 3-(2-ethyl-[1,3]dioxolan-2-yl)benzaldehyde in 50 ml ofTHF is then added drop by drop, and the medium is stirred for 2 hours at0° C. After the usual treatment, the residue is purified bychromatography on a silica column (eluent heptane 80—ethyl acetate 20).A yellow oil is obtained (m=9.6 g; Y=89%).

[0095] (d) Dimethyl4-{2-[3-(2-ethyl[1,3]dioxolan-2-yl)-phenyl]ethyl}phthalate

[0096] 9.5 g (24 mmol) of dimethyl4-{(E)-2-[3-(2-ethyl-[1,3]dioxolan-2-yl )-phenyl]ethyl}phthalate aredissolved in a mixture of 120 ml of ethyl acetate and 5 ml oftriethylamine. The reaction mixture is degassed with a flow of nitrogenfor 10 minutes, then 1 g of 5% palladium on carbon is added. Thereaction medium is then heated to 80° C. while a pressure of 4 bar ofhydrogen is applied for 4 hours. The medium is then filtered andconcentrated under reduced pressure. The residue is purified bychromatography on a silica column. A colorless oil is obtained (m=7.5 g;Y=80%).

[0097] (e)(4-{2-[3-(2-Ethyl[1,3]dioxolan-2-yl)phenyl]ethyl}-2-hydroxymethylphenyl)methanol

[0098] 2.9 g (75 mmol) of lithium aluminum hydride are suspended in 20ml of ethyl ether. A solution of 7.5 g (19 mmol) of dimethyl4-{2-[3-(2-ethyl[1,3]dioxolan-2-yl)phenyl]ethyl}phthalate in 100 ml ofethyl ether is added drop by drop. After stirring at ambient temperaturefor 20 minutes, the reaction medium is treated by addition of 15 ml ofwater, 1.5 ml of 15% sodium carbonate and 4.5 ml of water, then filteredand concentrated under reduced pressure. A colorless oil is obtained(m=6.4 g; Y=99%).

[0099] (f) 1-{3-[2-(3,4-Bis-hydroxymethylphenyl)ethyl]-phenyl}propan-1-one

[0100] 6.4 g (18.7 mmol) of(4-{2-[3-(2-ethyl-[1,3]dioxolan-2-yl)phenyl]lethyl}2-hydroxymethyl-phenyl)methanolare dissolved in a mixture of 40 ml of water and 40 ml of acetone. 650mg of paratoluene-sulfonic acid are added, and the medium is stirred for5 hours. After the usual treatment, the desired product is pure withoutpurification, and obtained in the form of colorless oil (m=5.57 g;Y=100%).

[0101] (g)1-(3-{2-[3,4-Bis(tert-butyldimethylsilanyloxy-methyl)phenyl]ethyl}phenyl)propan-1-one

[0102] 5.5 g (18.5 mmol) of 1-{3-[2-(3,4-bishydroxy-methylphenyl)ethyl]phenyl}propan-1-one are dissolved in 50 ml of anhydrous DMF, andthe mixture is cooled to 0° C. 6.7 g (45 mmol) oftert-butyldimethylchlorosilane and 3.5 g (52 mmol) of imidazole areadded. The medium is brought back to ambient temperature and is stirredfor 2 h. After treatment with a saturated solution of ammonium chlorideand then extraction with ethyl acetate, the organic phases arecollected, rinsed with water, dried and concentrated under reducedpressure. A colorless oil is obtained (m=9.6 g; Y=99%).

[0103] (h) Ethyl(E)-3-(3-{2-[3,4-bis(tert-butyldimethyl-silanyloxymethyl)phenyl]ethyl}phenyl)pent-2-enoat

[0104] 11.1 ml (56 mmol) of triethyl phosphono-acetate are dissolved in100 ml of THF. 2.2 g (55 mmol) of 60% sodium hydride are then added, andthe medium is stirred for 30 minutes at ambient temperature. A solutionof 9.5 g (18 mmol) of1-(3-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl]ethyl}phenyl)-propan-1-one in 100 ml of THF is then added drop bydrop. The medium is stirred for 6 hours, then treated with water andextracted with ethyl acetate. The residue obtained is purified bychromatography on silica gel (eluent ethyl acetate 10-heptane 90). Ayellow oil is obtained (m=5.8 g; Y=56%).

[0105] (i)(E)-3-(3-{2-[3,4-Bis(tert-butyldimethylsilanyloxy-methyl)phenyl]ethyl}phenyl)pent-2-en-1-ol

[0106] 0.75 g (19 mmol) of lithium aluminum hydride are suspended in 10ml of ethyl ether. A solution of 5.6 g (9.6 mmol) of ethyl(E)-3-(3-{2-[3,4-bis(tert-butyldimethylsilanyloxmethly)phenyl]ethyl}phenyl)pent-2-enoatein 50 ml of ethyl ether is added drop by drop. After stirring at ambienttemperature for 20 minutes, the reaction medium is treated by additionof 0.75 ml of water, 0.75 ml of 15% sodium carbonate and 1.5 ml ofwater, then filtered and concentrated under reduced pressure. Acolorless oil is obtained (m=5.26 g; Y=99%).

[0107] (j) (E)-3-(3-{2-[3,4-Bis(tert-butyldimethylsilanyloxy-methyl)phenyl]ethyl}phenyl)pent-2-enal

[0108] 2.8 g (5 mmol) of(E)-3-(3-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl]ethyl}phenyl)pent-2-en-1-olare dissolved in 50 ml of dichloromethane. 4.3 g (50 mmol) of manganesedioxide are added, and the reaction medium is stirred for 12 hours, thenfiltered and concentrated under reduced pressure. The desired product isobtained in the form of yellow oil (m=2.8 g; Y=100%).

[0109] (k) Ethyl(2E,4E)-5-(3-{2-[3,4-bis(tert-butyldimethyl-silanyloxymethyl)phenyl]ethyl)phenyl)hepta-2,4-dienoate

[0110] 1.3 ml (6.4 mmol) of triethyl phosphono-acetate are dissolved in20 ml of THF. 260 mg (6.5 mmol) of 60% sodium hydride are then added,and the medium is stirred for 30 minutes at ambient temperature. Asolution of 2.8 g (5 mmol) of(E)-3-(3-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)-phenyl]ethyl}phenyl)pent-2-enalin 30 ml of THF is then added drop by drop. The medium is stirred for 6hours, then treated with water and extracted with ethyl acetate. Theresidue obtained is purified by chromatography on silica gel (eluentethyl acetate 10-heptane 90). A yellow oil is obtained (m=2.52 g;Y=81%).

[0111] (l)(4E,6E)-7-{3-[2-(3,4-Bis-hydroxymethylphenyl)-ethyl]phenyl}-3-ethylnon4,6-dien-3-ol

[0112] 1.7 g (2.7 mmol) of ethyl(2E,4E)-5[-(3-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)ethyl}phenyl)hepta-2,4-dienoate are dissolved in 120 ml of anhydrous THF, andthe mixture is cooled to −78° C. 13.5 ml (13.5 mmol) of a solution ofethyllithium (1.0-1.5 M) are added, and the medium is stirred at thistemperature for 1 hour, then brought back to 0° C. and treated with asaturated solution of ammonium chloride. The residue obtained isdissolved in 50 ml of THF and then 6.5 ml (6.5 mmol) of a solution oftetrabutylammonium fluoride is added. After stirring for 30 minutes andthe usual treatment, the residue obtained is purified by chromatographyon a silica column. The desired product is obtained in the form ofcolorless oil (m=200 mg; Y=18%).

[0113]¹H NMR (DMSO): 0.82 (t, 6H, J=7.5 Hz); 0.89 (t, 3H, J=7.4 Hz);1.41-1.53 (m, 4H); 2.41 (q, 2H, J=7.4 Hz); 2.83 (s, 4H); 4.01 (s, 1H);4.41 (t, 2H, J=8 Hz); 4.45 (t, 2H, J=8 Hz); 4.94-4.98 (m, 2H); 6.31 (d,1H, J=15.0 Hz); 6.46 (d, 1H, J=11.0 Hz); 7.08-7.29 (m, 7H); 7.42-7.45(m, 1H).

EXAMPLE 2

[0114](E)-6-[3-{3,4-Bis-hydroxymethylbenzyloxy)phenyl]-1,1,1-trifluoro-2-tifluoromethyloct-5-en-3-yn-2-ol

[0115] (a) 3-(tert-butyldimethylsilanyloxy)benzaldehyde

[0116] In a manner analogous to example 1 g, by reaction of 42.7 g(0.275 mol) of tert-butyldimethylchlorosilane with 30.5 g (0.2 mol) of3-hydroxybenzaldehyde and (20.4 g, 0.3 mol) of imidazole. Afterpurification on a silica column (dichloromethane 20-heptane 80), ayellow oil is obtained (m=55.9 g; Y=95%).

[0117] (b) 1-[3-(tert-Butyldimethylsilanyloxy)phenyl]propan-1-ol

[0118] 50 g (0.21 mol) of 3-(tert-butyldimethyl-silanyloxy) benzaldehydeare dissolved in 500 ml of ethyl ether and the mixture is cooled to 0°C. 80 ml (0.24 mol) of a 3.0 M solution of ethylmagnesium bromide areadded slowly, and the mixture is stirred for 5 hours. After the usualtreatment, the residue obtained is purified by chromatography on asilica column (eluent ethyl acetate 20/hexane 80). A colorless oil isobtained (m=45.8 g; Y=82%).

[0119] (c) 1-[3-(tert-Butyldimethylsilanyloxy)phenyl]propan-1-one

[0120] In a manner analogous to example 1j, by reaction of 45 g (0.17mol) of 1-[3-(tert-butyldimethylsilanyloxy) phenyl]propan-1-ol with (148g, 1.7 mol) of manganese dioxide. A yellow oil is obtained (m=45 g,Y=100%).

[0121] (d) Ethyl(E)-3-[3-(tert-butyldimethylsilanyloxy)-phenyl]pent-2-enoate

[0122] 22.5 ml (113 mmol) of triethyl phosphono-acetate are dissolved in100 ml of THF. 4.5 g (113 mmol) of 60% sodium hydride are then added,and the medium is stirred for 30 minutes at ambient temperature. Asolution of 20 g (75.6 mmol) of3-(tert-butyldimethylsilanyloxy)propan-1-one in 100 ml of THF is thenadded drop by drop. The medium is stirred for 6 hours, then treated withwater and extracted with ethyl acetate. The residue obtained is purifiedby chromatography on silica gel (eluent ethyl acetate 10-heptane 90). Ayellow oil is obtained (m=7.6 g; Y=30%).

[0123] (e) (E)-3-[3-(tert-Butyldimethylsilanyloxy)phenyl]pent-2-en-1-ol

[0124] In a manner analogous to example 1e, by reaction of 7.6 g (23mmol) of ethyl (E)-3-[3-(tert-butyldimethylsilanyloxy)phenyl]pent-2-enoate with 1.05 g (25 mmol) of lithium aluminum hydride.A colorless oil is obtained (m=6.7 g; Y=100%).

[0125] (f) (E)-3-[3-(tert-Butyldimethylsilanyloxy)phenyl]pent-2-en-1-al

[0126] In a manner analogous to example 1j, by reaction of 6.7 g (23mmol) of (E)-3-[3-(tert-butyldimethylsilanyloxy)phenyl]pent-2-en-1-olwith 10 g (115 mmol) of manganese dioxide. A yellow oil is obtained(m=4.7 g; Y=71%).

[0127] (g)tert-Butyl-[3-((E)-4,4-dibromo-1-ethylbuta-1,3-dienyl)phenoxy]dimethylsilane

[0128] 1.17 g (18 mmol) of zinc powder, 4.7 g (18 mmol) oftriphenylphosphine and 5.9 g (18 mmol) of carbon tetrabromide arestirred for 45 minutes in 150 ml of dichloromethane. A solution of 2.6 g(9 mmol) of (E)-3-[3-(tert-butyldimethylsilanyloxy)phenyl]pent-2-en-1-alin 10 ml of dichloromethane is added drop by drop. The reaction mediumis stirred for 1 hour, then extracted with a mixture of water and ofdichloro-methane. The residue is filtered on a silica column (eluentdichloromethane). A yellow oil is obtained (m=3.3 g; Y=83%).

[0129] (h)tert-Butyl-[3-((E)-1-ethylbut-1-en-3-ynyl)phenoxy]-dimethylsilane

[0130] 3.2 g (7.2 mmol) oftert-butyl-[3-((E)-4,4-dibromo-1-ethylbuta-1,3-dienyl)phenoxy]dimethylsilaneare dissolved in 50 ml and the mixture is cooled to −78° C. 5.7 ml (14.4mmol) of a 2.5 M solution of butyllithium are added and the medium isstirred for 2 hours, then it is treated with a saturated solution ofammonium chloride. The residue is purified by chromatography on a silicacolumn. A yellow oil is obtained (m=1.0 g; Y=49%).

[0131] (i) 3-((E)-1-Ethylbut-1-en-3-ynyl)phenol

[0132] 1 g (3.5 mmol) oftert-butyl-[3-((E)-1-ethylbut-1-en-3-ynyl)phenoxy]dimethylsilane isdissolved in 50 ml of THF, and 3.8 ml (38 mmol) of a 1.0 M solution oftetrabutylammonium fluoride are added drop by drop. The mixture isstirred for 30 minutes, then treated with a saturated solution ofammonium chloride and extracted with ethyl acetate. A yellow oil isobtained (m=690 mg; Y=100%).

[0133] (j)2-Benzoyloxymethyl-5-[3-((E)-1-ethylbut-1-en-3-ynyl)phenoxymethyl]benzylbenzoate

[0134] 610 mg (3.5 mmol) of 3-((E)-1-ethylbut-1-en-3-ynyl)phenol aredissolved in 80 ml of DMF. 150 mg (3.7 mmol) of sodium hydride areadded, and the mixture is stirred at ambient temperature. 1.5 g (6.2mmol) of 2-benzoyloxymethyl-5-bromomethylbenzyl benzoate are then added,and the medium is stirred for 2 hours. After the usual treatment andpurification by chromatography on a silica gel column, a colorless oilis obtained (m=1.66 g; Y=88%).

[0135] (k)1-(3,4-Bis-tert-butyldimethylsilyloxymethylbenzyl-oxy)-3-((E)-1-ethylbut-1-en-3-ynyl)benzene

[0136] 1.6 g (3 mmol) of2-benzoyloxymethyl-5-[3-((E)-1-ethylbut-1-en-3-ynyl)phenoxymethyl]benzylbenzoate are dissolved in 15 ml of a 2% solution of potassium carbonatein methanol. The reaction medium is stirred for 2 hours, then treatedwith a saturated solution of ammonium chloride, and extracted with ethylacetate. The residue obtained is dissolved in 20 ml of anhydrous DMF,and 900 mg (6 mmol) of tertbutyl-dimethylchlorosilane and 450 mg (6.6mmol) of imidazole are added. The medium is stirred for 10 hours atambient temperature. After the usual treatment, the residue obtained ispurified by chromatography on a silica column (eluent heptane 85-ethylacetate 85). An orange oil is obtained (m=1.16 g; Y=70%).

[0137] (l)(E)-6-{3-[3,4-Bis(tert-butyldimethylsilanyloxy-methyl)benzyloxy]phenyl}-1,1,1-trifluoro-2-trifluoro-methyloct-5-en-3-yn-2-ol

[0138] 1.16 g (2.1 mmol) of1-(3,4-bis-tert-butyl-dimethylsilyloxymethylbenzyloxy)-3-((E)-1-ethylbut-1-en-3-ynyl)benzene are dissolved in 30 ml of anhydrous THF,and the mixture is cooled to −78° C. 930 μl (2.3 mmol) of a 2.5 Msolution of butyllithium are added drop by drop, and the medium isstirred for 15 minutes. A flow of hexafluoroacetone (gas) is passed intothe solution for 10 minutes, and the reaction medium is treated with asaturated solution of ammonium chloride. The residue obtained ispurified by chromatography on a silica column (eluent heptane 80-ethylacetate 20). A yellow oil is obtained (m=1.35 g; Y=89%).

[0139] (m)(E)-6-[3-(3,4-Bis-hydroxymethylbenzyloxy)phenyl]-1,1,1-trifluoro-2-trifluoro-methyloct-5-en-3-yn-2-ol

[0140] In a manner analogous to example 2i, by reaction of 350 mg (0.5mmol) of(E)-6-{3-[3,4-bis(tert-butyldimethylsilanyloxymethyl)benzyloxy]-phenyl}1,1,1-trifluoro-2-trifluoromethyloct-5-en-3-yn-2-olwith 1.2 ml (1.2 mmol) of a 1.0 M solution of tetrabutylammoniumfluoride. A colorless oil is obtained (m=210 mg; Y=80%).

[0141]¹H NMR (CDCl₃): 1.05 (t, 3H, J=7.4 Hz); 2.72 (q, 2H, J=7.4 Hz);4.74 (s, 4H); 5.05 (s, 2H); 5.69 (s, 1H); 6.91-7.01 (m, 3H); 7.24 (m,1H); 7.37 (s, 2H); 7.42 (s, 1H).

EXAMPLE 3 (3E,5E)-6-[3-(3,4-Bis-hydroxymethylbenzyloxy)pheny]-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol

[0142] (a)(3E,5E)-6-{3-[3,4-Bis(tert-butyldimethylsilanyloxy-methyl)benzyloxy]phenyl}-1,1,1-trifluoro-2-trifluoro-methylocta-3,5-dien-2-ol

[0143] 135 mg (3.55 mmol) of lithium aluminum hydride are dissolved in10 ml of anhydrous THF. 385 mg (7.1 mmol) of sodium methoxide are added,and the mixture is stirred at ambient temperature for 10 minutes. Asolution of 860 mg (1.2 mmol) of(E)-6-{3-[3,4-bis(tertbutyldimethylsilanyloxymethyl)-benzyloxy]phenyl}-1,1,1-trifluoro-2-trifluoro-methyloct-5-en-3 -yn-2-ol (described in example21) in 7 ml of THF is added drop by drop. The medium is heated to refluxfor 2 hours, then treated by successive addition of 120 μl of water, 120μl of 15% NaOH and 35 μl of water. After filtration, a thick yellowishoil is obtained (m=650 mg; Y=76%).

[0144] (b)(3E,5E)-6-[3-(3,4-Bis-hydroxymethylbenzyloxy)-phenyl]-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol

[0145] In a manner analogous to example 2m, by reaction of 640 mg (0.89mmol) of(3E,5E)-6-{3-[3,4-bis(tert-butyldimethylsilanyloxymethyl)benzyloxy]-phenyl}1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-olwith 2.1 ml (2.1 mmol) of a 1.0 M solution of tetrabutylammoniumfluoride. A colorless oil is obtained (m=260 mg; Y=60%).

[0146]¹H NMR (DMSO): 1.10 (t, 3H, J=7.5 Hz); 2.65 (q, 2H, J=7.4 Hz);4.55 (t, 4H, J=5.2 Hz); 5.08-5.17 (m, 4H); 6.05 (d, 1H, J=15.1 Hz); 6.64(d, 1H, J=11.2 Hz); 6.96 (dd, 1H, J1=11.2 Hz, J2=2 Hz);7.08-7.08-7.51(m, 6H); 8.27 (s, 1H).

EXAMPLE 4(E)-6-{3-[2-(3,4-Bis-hydroxymethylphenyl)ethyl]phenyl}-1,1,1-trifluoro-2-trifluoromethyloct-5-en-3-yn-2-ol

[0147] (a)(E)-1-(3-{2-[3,4-Bis(tert-butyldimethylsilanyloxy-methyl)phenyl]ethyl}phenyl)-4,4-dibromo-1-ethylbuta-1,3-diene

[0148] In a manner analogous to example 2g, by reaction of 9 g (16.3mmol) of(E)-3-(3-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)-phenyl]ethyl}phenyl)pent-2-enal(prepared in example 1j) with 2.1 g (32.5 mmol) of zinc powder, 8.5 g(32.5 mmol) of triphenylphosphine and 108 g (32.5 mmol) of carbontetrabromide. A yellow oil is obtained (m=11.3 g; Y=98%).

[0149] (b)(E)-1-(3-{2-[3,4-Bis(tert-butyldimethylsil˜yloxy-methyl)phenyl]ethyl}phenyl)-1-ethylbut-1-en-3-yne

[0150] In a manner analogous to example 2 h, by reaction of 11.3 g (15.9mmol) of(E)-1-(3-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)-phenyl]ethyl}phenyl)-4,4-dibromo-1-ethylbuta-1,3-dienewith 128 ml (32 mmol) of a 2.5 M solution of butyllithium. A yellow oilis obtained (m=85 g; Y=97%).

[0151] (c)(E)-6-(3-{2-[3,4-Bis(tert-butyldimethylsilanyloxy-methyl)phenyl]ethyl}phenyl)-1,1,1-trifluoro-2-tri-fluoromethyloct-5-en-3-yn-2-ol

[0152] In a manner analogous to example 21, by reaction of 5 g (9.1mmol) of(E)-1-(3-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)-phenyl]ethyl}phenyl)-1-ethyl-but-1-en-3-ynewith 4 ml (10 mmol) of a 2.5 M solution of butyllithium and a flow ofhexafluoroacetone. The desired product is obtained in the form of ayellow oil (m=3.7 g; Y=57%).

[0153] (d)(E)-6-(3-[2-(3,4-Bis-hydroxymethylphenyl)ethyl]-phenyl)-1,1,1-trifluoro-2-trifluoromethyloct-5-en-3-yn-2-ol

[0154] In a manner analogous to example 2m, by reaction of 1 g (1.4mmol) of(E)-6-(3-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl]lethyl}-phenyl)-1,1,1-trifluoro-2-trifluoromethyloct-5-en-3-yn-2-olwith 3.3 ml (3.3 mmol) of a 1.0 M solution of tetrabutylammoniumfluoride. A yellowish solid is obtained (m.p.=123° C.; m=570 mg; Y=84%).

[0155]¹H NMR (CDCl₃): 1.05 (t, 3H, J=7.5 Hz); 2.75 (q, 2H, J=7.5 Hz);2.92 (s, 4H); 4.69 (s, 4H); 5.67 (s, 1H); 7.05-7.31 (m, 7H).

EXAMPLE 5 (3E, 5E)-6-{3-[2-(3,4-Bis-hydroxymethylphenyl)ethyl]-phenyl}-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol

[0156] (a)(3E,5E)-6-(3-{2-[3,4-Bis(tert-butyldimethyl-silanyloxymethyl)phenyl]ethyl}phenyl)-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol

[0157] In a manner analogous to example 3a, by reaction of 2.5 g (3.5mmol) of(E)-6-(3-(2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl]ethyl}-phenyl)-1,1,1-trifluoro-2-trifluoromethyloct-5-en-3-yn-2-ol(described in example 4c) with 400 mg (10.4 mmol) of lithium aluminumhydride and 1.13 g (21 mmol) of sodium methoxide. A yellow oil isobtained (m=1.27 g; Y=51%).

[0158] (b)(3E,5E)-6-{3-[2-(3,4-Bis-hydroxymethylphenyl)ethyl]-phenyl}1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol

[0159] In a manner analogous to example 2m, by reaction of 1.2 g (1.67mmol) of(3E,5E)-6-(3-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl]ethyl}phenyl)-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol with 4 ml (4 mmol) ofa 1.0 M solution of tetrabutylammonium fluoride. A white solid isobtained (m.p.=104° C; m=715 mg; Y=87%).

[0160]¹H NMR (DMSO): 1.02 (t, 3H, J=7.5 Hz); 2.66 (q, 2H, J=7.5 Hz);2.93 (s, 4H); 4.71 (s, 2H); 4.72 (s, 2H); 5.79 (d, 1H, J=15.0 Hz); 6.24(d, 1H, J=11.0 Hz); 7.08-7.30 (m, 8H).

EXAMPLE 6 Formulation Examples

[0161] 1) Oral Route:

[0162] (a) The following composition is prepared in the form of a 0.2 gtablet: Compound of Example 1 0.005 g Pregelatinized starch 0.065 gMicrocrystalline cellulose 0.075 g Lactose 0.050 g Magnesium stearate0.005 g

[0163] For the treatment of ichthyosis, 1 to 3 tablets per day areadministered to an adult individual for 1 to 12 months according to theseverity of the case treated.

[0164] (b) A drinkable suspension is prepared, intended to be formulatedin 5 ml ampoules: Compound of example 2 0.050 mg Glycerol 0.500 g 70%sorbitol 0.500 g Sodium saccharinate 0.010 g Methyl parahydroxybenzoate0.040 g Flavoring q.s. Purified water q.s. 5 ml

[0165] For the treatment of acne, 1 ampoule per day is administered toan adult individual for 1 to 12 months according to the severity of thecase treated.

[0166] (c) The following formulation is prepared which is intended to beformulated in gelatine capsules: Compound of example 4 0.0001 mg Maizestarch 0.060 g Lactose q.s 0.300 g

[0167] The gelatine capsules used are formed of gelatine, of titaniumoxide and of a preservative.

[0168] In the treatment of psoriasis, 1 gelatine capsule per day isadministered to an adult individual for 1 to 12 months.

[0169] (d) The following formulation is prepared which is intended to beformulated in gelatine capsules: Compound of example 5 0.02 mgCyclosporin 0.050 g Maize starch 0.060 g Lactose q.s. 0.300 g

[0170] The gelatine capsules used are formed of gelatine, of titaniumoxide and of a preservative.

[0171] In the treatment of psoriasis, 1 gelatine capsule per day isadministered to an adult individual for 1 to 12 months.

[0172] 2) Topical Route:

[0173] (a) The following nonionic water-in-oil cream is prepared:Compound of example 3 0.100 g Mixture of alcohols of emulsive 39.900 glanolin, of waxes and of refined oils, sold by BDF under the name“Eucerine anhydre” Methyl parahydroxybenzoate 0.075 g Propylparahydroxybenzoate 0.075 g Sterile demineralized water q.s 100.000 g

[0174] This cream is applied to a psoriatic skin 1 to 2 times per dayfor 1 to 12 months.

[0175] (b) A gel is prepared by producing the following formulation:Compound of example 1 0.001 g Erythromycin base 4.000 gButylhydroxytoluene 0.050 g Hydroxypropylcellulose sold by Herculesunder the 2.000 g name of “KLUCEL HF” Ethanol (to 95″) q.s 100.000 g

[0176] This gel is applied to a skin affected by dermatosis or an acneicskin 1 to 3 times per day for 6 to 12 weeks according to the severity ofthe case treated.

[0177] (c) An antiseborrheic lotion is prepared by proceeding to mix thefollowing ingredients: Compound of example 2 0.030 g Propylene glycol5.000 g Butylhydroxytoluene 0.100 g Ethanol (to 95°) q.s 100.000 g

[0178] This lotion is applied two times per day to a seborrheic scalpand a significant improvement is confirmed within a period of between 2and 6 weeks.

[0179] (d) A cosmetic preparation against the harmful effects of the sunis prepared by proceeding to mix the following ingredients: Compound ofexample 2 1.000 g Benzylidenecamphor 4.000 g Fatty acid triglycerides31.000 g Glycerol monostearate 6.000 g Stearic acid 2.000 g Cetylalcohol 1.200 g Lanolin 4.000 g Preservatives 0.300 g Propylene glycol2.000 g Triethanolamine 0.500 g Perfume 0.400 g Demineralized water q.s100.000 g

[0180] This composition is applied daily, it allows photoinduced agingto be combated.

[0181] (e) The following nonionic Oil-in-Water cream is prepared:Compound of example 3 0.500 g Retinoic acid 0.020 g Cetyl alcohol 4.000g Glycerol monostearate 2.500 g Propyl parahydroxybenzoate 0.075 g PEG50 stearate 2.500 g Shea butter 9.200 g Propylene glycol 2.000 g Methylparahydroxybenzoate 0.075 g Sterile demineralized water q.s 100.000 g

[0182] This cream is applied to a psoriatic skin 1 to 2 times per dayfor 30 days for attack treatment and indefinitely for maintenance.

[0183] (f) A topical gel is prepared by proceeding to mix the followingingredients: Compound of example 4 0.050 g Ethanol 43.000 g α-tocopherol0.050 g Carboxyvinyl polymer sold under the 0.500 g name “Carbopol 941”by “Goodrich” Triethanolamine in aqueous solution 3.800 g at 20% byweight Water 9.300 g Propylene glycol q.s. 100.000 g

[0184] This gel is applied in the treatment of acne 1 to 3 times per dayfor 6 to 12 weeks according to the severity of the case treated.

[0185] (g) A lotion against hair loss and for the regrowth of the hairis prepared by proceeding to mix the following ingredients: Compound ofexample 3 0.05 g Compound sold under the 1.00 g name “MinoxidilPropylene glycol 20.00 g Ethanol 34.92 g Polyethylene glycol (molecular40.00 g mass = 400) Butylhydroxyanisole 0.01 g Butylhydroxytoluene 0.02g Water q.s. 100.00 g

[0186] This lotion is applied 1 to 2 times per day for 3 months on ascalp which has suffered a loss of hair and indefinitely for maintenancetreatment.

[0187] (h) An antiacneic cream is prepared by proceeding to mix thefollowing ingredients: Compound of example 5 0.050 g Retinoic acid 0.010g Mixture of stearates of glycerol and of 15.000 g polyethylene glycol(75 mol) sold under the name of “Gelot 64” by “GATTEFOSSE” Stone oilpolyoxyethylenated with 6 mol of 8.000 g ethylene oxide sold under thename of “Labrafil M2 130 CS” by “GATTEFOSSE” Perhydrosqualene 10.000 gPreservatives q.s. Polyethylene glycol (molecular mass = 400) 8.000 gEthylenediaminetetraacetic acid disodium salt 0.050 g Purified waterq.s. 100.000 g

[0188] This cream is applied to a skin affected by dermatosis or anacneic skin 1 to 3 times per day for 6 to 12 weeks.

[0189] (i) An oil-in-water cream is prepared by producing the followingformulation: Compound of example 4 0.020 g Betamethasone 17-valerate0.050 g S-carboxymethylcysteine 3.000 g Polyoxyethylene stearate (40 molof ethylene 4.000 g oxide) sold under the name of “Myrj 52” by “ATLAS”Sorbitan monolaurate, polyoxyethylenated with 1.800 g 20 mol of ethyleneoxide sold under the name of “Tween 20”by “ATLAS” Mixture of glycerylmono- and distearate sold 4.200 g under the name of “Geleol” by“GATTEFOSSE” Propylene glycol 10.000 g Butylhydroxyanisole 0.010 gButylhydroxytoluene 0.020 g Cetostearyl alcohol 6.200 g Preservativesq.s. Perhydrosqualene 18.000 g Mixture of caprylic-capric triglyceridessold 4000 g under the name of “Myglyol 8 12” by “DYNAMIT NOBEL”Triethanolamine (99% by weight) Water q.s. 100.000 g

[0190] This cream is applied 2 times per day to a skin affected byinflammatory dermatosis for 30 days.

[0191] (i) The following oil-in-water-type cream is prepared: Lacticacid 5.000 g Compound of example 1 0.020 g Polyoxyethylene stearate (40mol of ethylene 4.000 g oxide) sold under the name “Myrj 52” by thecompany “ATLAS” Sorbitan monolaurate, polyoxyethylenated with 1.800 g 20mol of ethylene oxide sold under the name of “Tween 20” by the company“ATLAS” Mixture of glyceryl mono- and distearate sold 4.200 g under thename “Geleol” by the company “GATTEFOSSE” Propylene glycol 10.000 gButylhydroxyanisole 0.010 g Butylhydroxytoluene 0.020 g Cetostearylalcohol 6.200 g Preservatives q.s. Perhydrosqualene 18.000 g Mixture ofcaprylic-capric triglycerides sold 4.000 g under the name of “Miglyol 812” by the company “DYNAMIT NOBEL” Water q.s 100.000 g

[0192] This cream is applied once per day, it helps combat aging,whether photoinduced or chronological.

[0193] (k) The following anhydrous salve is prepared: Compound ofexample 1 5.000 g Liquid petroleum jelly 50.00 g Butylhydrotoluene 0.050g White petroleum jelly q.s 100 g

[0194] This salve is applied twice per day to a skin affected bysquamous dermatosis for 30 days.

[0195] 3) Intralesional Route:

[0196] (a) The following composition is prepared: Compound of example 20.002 g Ethyl oleate q.s. 10 g

[0197] In the treatment of malignant melanoma, the composition isinjected into an adult individual at a rate of 1 to 7 times per week for1 to 12 months.

[0198] (b) The following composition is prepared: Compound of example 10.050 g Olive oil q.s. 2 g

[0199] In the treatment of basocellular carcinoma, the composition isinjected into an adult individual at a rate of 1 to 7 times per week for1 to 12 months.

[0200] (c) The following composition is prepared: Compound of example 30.1 mg Sesame oil q.s. 2 g

[0201] In the treatment of spinocellular carcinoma, the composition isinjected into an adult individual at a rate of 1 to 7 times per week for1 to 12 months.

[0202] (d) The following composition is prepared: Compound of example 40.001 mg Methyl benzoate q.s. 10 g

[0203] In the treatment of carcinoma of the colon, the composition isinjected into an adult individual at a rate of 1 to 7 times per week for1 to 12 months.

[0204] 4) Intravenous Route:

[0205] (a) The following injectable lipid emulsion is prepared: Compoundof example 4 0.001 mg Soya oil 10.000 g Egg phospholipid 1.200 gGlycerol 2.500 g Water for injectable q.s.p. 100.000 g

[0206] In the treatment of psoriasis, the composition is injected intoan adult individual at a rate of 1 to 7 times per week for 1 to 12months.

[0207] (b) The following injectable lipid emulsion is prepared: Compoundof example 1  0.010 g Cotton oil  10.000 g Soya lecithin  0.750 gSorbitol  5.000 g DL, α tocopherol  0.100 g Water for injectable q.s.p.100.000 g

[0208] In the treatment of ichthyosis, the composition is injected intoan adult individual at a rate of 1 to 7 times per week for 1 to 12months.

[0209] (c) The following injectable lipid emulsion is prepared: Compoundof example 2  0.001 g Soya oil  15.000 g Acetylated monoglycerides 10.000 g Pluronic F-108  1.000 g Glycerol  2.500 g Water for injectableq.s.p 100.000 g

[0210] In the treatment of leukemia, the composition is injected into anadult individual at a rate of 1 to 7 times per week for 1 to 12 months.

[0211] (d) The following mixed micelle composition is prepared: Compoundof example 2  0.001 g Lecithin  16.930 g Glycocholic acid  8.850 g Waterfor injectable q.s.p. 100.000 g

[0212] In the treatment of malignant melanoma, the composition isinjected into an adult individual at a rate of 1 to 7 times per week for1 to 12 months.

[0213] (e) The following cyclodextrin composition is prepared:Composition of example 3 0.1 mg beta-cyclodextrin 0.100 g Water forinjectable q.s.p. 10.000 g

[0214] In the treatment of transplant rejection, the composition isinjected into an adult individual at a rate of 1 to 7 times per week for1 to 12 months.

[0215] (f) The following cyclodextrin composition is prepared: Compoundof example  0.010 g 2-hydroxypropylcyclodextrin  0.100 g Water forinjectable q.s.p 10.000 g

[0216] In the treatment of cancer of the kidney, the composition isinjected into an adult individual at a rate of 1 to 7 times per week for1 to 12 months.

EXAMPLE 7 Example of Evaluation Test of the Biological Activity of theCompounds of the Invention: Transactivation Potential

[0217] The VDR agonist activity can be tested on the HeLa cell line, bycotransfection of an expression vector of the human VDR receptor and ofthe p240Hase-CAT reporter plasmid which contains the region −1399 to +76of the rat 24-hydroxylase promoter, cloned upstream of the phase codingfor the chloramphenicol acetyltransferase (CAT) gene. 18 hours aftercotransfection, the test product is added to the medium. After treatmentfor 18 hours, the measurement of the CAT activity of the cell lysates iscarried out by means of an Elisa test (Enzyme Linked Immuno SorbentEssay, test marketed by Roche Molecular Biochemicals). The agonistactivity can be characterized in this cotransfection system by thedetermination of the dose necessary in order to obtain 50% of themaximum activity of the product (AC50). TABLE 1 COMPOUND AC50 nM Example1 39 Example 59 of D1 124 Example 2 77 Example 80 of D1 746 Example 3 7Example 92 of D1 79 Example 4 16 Example 80 of D1 746 Example 5 3Example 60 of D1 319

[0218] Each compound according to the invention has been compared to thestructurally closest compound protected in WO 00/26167 (D1). Tofacilitate the comparison, the structures of the compounds of theinvention and of the comparative examples of D1 are assembled in theFIGS. 5 and 6. The results show the significantly stronger activity ofthe compounds of the invention with respect to the compounds of D1. Adifference between two values of AC50 is considered as significant if itis at least a factor of 3, preferentially a factor of 5 and morepreferentially a factor of 10.

EXAMPLE 8 Example of Evaluation Test of the Biological Activity of theCompounds of the Invention: Activity on the Proliferation of HumanKeratinocytes

[0219] It is known that 1,25-dihydroxyvitamin D3, called calcitriol andcorresponding to natural vitamin D, inhibits the proliferation of humankeratinocytes in culture. The method used is the following: the normalhuman keratinocytes are inoculated at low density into a 24-well plate.After 4 hours, the compounds to be tested are added to the culturemedium. After culturing for 5 days, the proliferation of thekeratinocytes is determined by incorporation of 5-bromo-2′ deoxyuridine(BrdU) in the DNA. The quantity of BrdU incorporated is then quantifiedby using the Elisa test (Enzyme Linked Immuno Sorbent Essay, testmarketed by Roche Molecular Biochemicals).

[0220] The inhibitory effect on the proliferation of the keratinocytesof the compounds according to the invention and of the calcitriol usedas a reference compound is summarized in table II which follows. The Ic50 value indicates the concentration of compound tested for which thecompound inhibits the proliferation of the keratinocytes by 50%.

[0221] These results allow an inhibitory activity on the proliferationof the keratinocytes to be demonstrated for the compounds according tothe invention in the same ranges of value as that of calcitriol (naturalvitamin D). In addition, the results show significant differencesbetween the compounds according to the invention and the structurallyclosest compounds of D1. A difference is considered as significantbetween two values of AC50 if it is at least a factor of 3,preferentially a factor of 5 and more preferentially a factor of 10.TABLE II INHIBITION OF PROLIFERATION COMPOUND IC50* (nM) Calcitriol 14Example 1 45 Example 80 of D1 1029 Example 2 153 Example 80 ofD1 >10,000 (nonactive) Example 3 35 Example 92 of D1 99 Example 4 29Example 80 of D1 >10,000 (nonactive) Example 5 8 Example 60 of D1 1506

EXAMPLE 9 Example of Evaluation Test of the Biological Activity of theCompounds of the Invention: Activity on the Differentiation of HL60Cells

[0222] Calcitriol induces the differentiation of promyelocytic leukemiacells (HL60) in monocytes/macrophages. This differentiation inductoreffect is a well-characterized marker of cellular vitamin D activity.One of the most important antimicrobial products of macrophages ishydrogen peroxide, which can be analyzed experimentally by the reductionof NBT (Nitroblue Tetrazolium).

[0223] The method used is the following: The HL60 cells are inoculatedinto 6-well plates and then treated immediately with the compounds to betested. After 4 days in culture, the cells are incubated with phorbolTPA ester and NBT for a short period and the differentiated cells, i.e.,positive to NBT, are counted.

[0224] The inductor effect of the differentiation on the HL60 cells,compounds according to the invention as well as that of the referencecompound calcitriol is clarified in table III below. TABLE III CompoundActivation of Differentiation AC 50? (nM) Calcitriol 7 (n = 5) Example 156 (n = 3) Example 59 of D1 310 Example 3 7 (n = 2) Example 5 5 (n = 2)

[0225] These results show that examples 3 and according to the inventionhave an induction of differentiation activity on HL60 cells similar tothat of calcitriol.

EXAMPLE 10 Example of Evaluation Test of the Biological Activity of theCompounds of the Invention: “In vivo” Induction of 24-hydroxylase in SKHMice

[0226] 24-Hydroxylase is a cytochrome P450 enzyme which hydroxylates1,25-dihydroxyvitamin D3 (calcitriol) in position 24 resulting in ametabolite 24,25-trihydroxy-vitamin D3. It has been shown by Voorheesand al. (JID 1997, 108: 513-518) that the expression of the24-hydroxylase gene was induced by calcitriol in human skin.

[0227] Consequently, the agonist activity on receptors of vitamin D ofthe compounds of the invention can be evaluated “in vivo” by inductionof 24-hydroxylase in SKH mice.

[0228] The method used is the following: XII mice receive a singletopical application of a compound to be tested in solution in ethanol atincreasing concentrations. A volume of 50 μl of the product to be testedor of the vehicle alone is applied on the back of the mice with the aidof a pipette.

[0229] Other SKH mice receive a single topical application of calcitriolin solution in ethanol at increasing concentrations. A volume of 50 μlof the product to be tested or of the vehicle alone is applied on theback of the mice with the aid of a pipette.

[0230] 8 hours after topical application, the mice are euthanized, thetreated skin is removed and the epidermidis is separated from thedermis. The quantification of the MRNA of the 24-Hydroxylase is carriedout by semiquantitative PCR. The results are standardized with respectto the expression of the mRNA of GAPDH and the values for the differentconcentrations of calcitriol tested and, for the different compounds ofthe invention tested, are expressed as an induction factor with respectto calcitriol.

[0231] The results are summarized in table IV which follows: TABLE IVMRNA EXPRESSION OF 24-HYDROXYLASE Concentration % Induction FactorVersus Compound Tested (weight/volume) Ethanol Calcitriol 0.0001 6.7Calcitriol 0.001 10.3 Calcitriol 0.01 20.1 Calcitriol 0.1 26

[0232] These results show that calcitriol administered by single topicalapplication induces the expression of the mRNA of 24-hydroxylase in theepidermidis in a dose-dependent manner in mice.

[0233] The biological activity of the compounds of the invention isevaluated by comparison between the induction factors obtained for thecompounds of the invention and the induction factors obtained forcalcitriol. The results are presented in table V which follows: TABLE VInduction in % vs Concentration % Induction Calcitriol Compound Tested(weight/volume) Tested at 0.01% Calcitriol 0.01 100 Example 1 0.1 108Example 2 0.01 58 Example 3 0.001 59 Example 4 0.01 89 Example 5 0.0003106

[0234] Thus, these results show that the examples according to theinvention have an activity comparable or very superior (examples 3 and5) to that of calcitriol.

[0235] Each patent, patent application, publication and literaturearticle/report cited or indicated herein is hereby expresslyincorporated by reference.

[0236] While the invention has been described in terms of variousspecific and preferred embodiments, the skilled artisan will appreciatethat various modifications, substitutions, omissions, and changes may bemade without departing from the spirit thereof. Accordingly, it isintended that the scope of the present invention be limited solely bythe scope of the following claims, including equivalents thereof.

What is claimed is:
 1. A vitamin D analog compound selected from thegroup consisting of(4E,6E)-7-{3-[2-(3,4-bis-hydroxymethylphenyl)-ethyl]phenyl}-3-ethylnona-4,6-dien-3-ol,(E)-6-[3-(3,4-bis-hydroxymethylbenzyloxy)phenyl]-1,1,1-trifluoro-2-trifluoromethyloct-5-en-3-yn-2-ol,(3E,5E)-6-[3-(3,4-bis-hydroxymethylbenzyloxy)-phenyl]1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol,(E)-6-{3-[2-(3,4-bis-hydroxymethylphenyl)ethyl]-phenyl}-1,1,1-trifluoro-2-trifluorometthyloct-5-en-3-yn-2-ol,and(3E,5E)-6-{3-[2-(3,4-bis-hydroxymethylphenyl)-ethyl]phenyl-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol, and the geometric isomers thereof and these compounds in which oneor more of the hydroxyl functions are protected by a protective group—(C═O)—R, in which R is a linear or branched alkyl radical having from 1to 6 carbon atoms, an aryl radical having from 6 to 10 carbon atoms, oran aralkyl radical having from 7 to 11 carbon atoms, the aryl radical orthe aralkyl radical optionally being mono-or disubstituted by a hydroxygroup, an alkoxy radical having from 1 to 3 carbon atoms, a halogenatom, a nitro function or by an amino function, and mixtures thereof. 2.The vitamin D analog compound as defined by claim 1, comprising at leastare protective group —(C═O)—R, in which R is a methyl, ethyl, isopropyl,tert-butyl or hexyl radical.
 3. The vitamin D analog compound as definedby claim 1, comprising at least one protective group —(C═O)—R, in whichR is a phenyl or naphthyl radical.
 4. The vitamin D analog compound asdefined by claim 1, comprising at least one protective group —(C═O)—R,in which R is a benzyl or methylnaphthyl radical.
 5. The vitamin Danalog compound as defined by claim 1, comprising at least oneprotective group —(C═O)—R, in which R is a fluorine, bromine or chlorineatom.
 6. A pharmaceutical composition comprising an effective cellproliferation and differentiation affecting amount of at least onevitamin D analog compound as defined by claim 1, formulated into apharmaceutically acceptable support therefor.
 7. The pharmaceuticalcomposition as defined by claim 6, further comprising at least oneretinoid, corticosteroid, estrogen, antioxidant, α-hydroxy acid,β-hydroxy acid, α-keto acid or derivative thereof, ion channel blocker,immune system affecting active agent, or mixture thereof.
 8. Thepharmaceutical composition as defined by claim 6, said at least onevitamin D analog compound comprising from 0.0001% to 5% by weightthereof.
 9. The pharmaceutical composition as defined by claim 6,formulated as tablets, capsules, a syrup, a suspension, a powder,granules, an emulsion, micropheres, nanospheres, controlled releaselipid vesicles or polymers, a solution, a salve, a cream, a milk, anointment, a lotion, a gel, a spray, or a swab.
 10. A cosmeticcomposition comprising a skin/hair cosmetically effective amount of atleast one vitamin D analog compound as defined by claim 1, formulatedinto a cosmetically acceptable support therefor.
 11. The cosmeticcomposition as defined by claim 10, further comprising at least oneretinoid, corticosteroid, antioxidant, α-hydroxy or α-keto acid orderivative thereof, ion channel blocker, or mixture thereof.
 12. Thecosmetic composition as defined by claim 10, said at least one vitamin Danalog compound comprising from 0.001% to 3% by weight thereof.
 13. Thecosmetic composition as defined by claim 10, formulated as a cream, alotion, a gel, microspheres, nanospheres, lipid or polymer vesicles, asoap, or a shampoo.
 14. A regime or regimen for influencing thetransactivation of vitamin D response elements in an individual in needof such treatment, comprising administering to such individual, a thuseffective amount of the pharmaceutical composition as defined by claim6.
 15. A regime or regimen for treating a dermatological complaint,condition or affliction associated with a keratinization disorder, on anindividual in need of such treatment, comprising administering to suchindividual, a thus effective amount of the pharmaceutical composition asdefined by claim
 6. 16. A regime or regimen for treating ichthyosis, anichthyosiform state, Darrier's syndrome, palmoplantar keratodermia,leucoplasia, a leucoplasiform state, or cutaneous or mucous (buccal)lichen, on an individual in need of such treatment, comprisingadministering to such individual, a thus effective amount of thepharmaceutical composition as defined by claim
 6. 17. A regime orregimen for treating a dermatological complaint, condition or afflictionhaving an inflammatory immunoallergic component, on an individual inneed of such treatment, comprising administering to such individual, athus effective amount of the pharmaceutical composition as defined byclaim
 6. 18. A regime or regimen for treating dermal or epidermalproliferation, on an individual in need of such treatment, comprisingadministering to such individual, a thus effective amount of thepharmaceutical composition as defined by claim
 6. 19. A regime orregimen for treating an immune dermatosis, on an individual in need ofsuch treatment, comprising administering to such individual, a thuseffective amount of the pharmaceutical composition as defined by claim6.
 20. A regime or regimen for treating a dermatological or generalcomplaint, condition or affliction having an immunological component onan individual in need of such treatment, comprising administering tosuch individual, a thus effective amount of the pharmaceuticalcomposition as defined by claim
 6. 21. A regime or regimen for treatinga sebaceous function disorder, on an individual in need of suchtreatment, comprising administering to such individual, a thus effectiveamount of the pharmaceutical composition as defined by claim
 6. 22. Aregime or regimen for treating a cutaneous disorder caused by UVradiation, or aging of the skin, on an individual in need of suchtreatment, comprising administering to such individual, a thus effectiveamount of the pharmaceutical composition as defined by claim
 6. 23. Aregime or regimen for treating a cicatrization disorder or stretchmarks, on an individual in need of such treatment, comprisingadministering to such individual, a thus effective amount of thepharmaceutical composition as defined by claim
 6. 24. A regime orregimen for treating an inflammatory complaint, condition or affliction,on an individual in need of such treatment, comprising administering tosuch individual, a thus effective amount of the pharmaceuticalcomposition as defined by claim
 6. 25. A regime or regimen for treatingan ophthalmological complaint, condition or affliction, on an individualin need of such treatment, comprising administering to such individual,a thus effective amount of the pharmaceutical composition as defined byclaim
 6. 26. A regime or regimen for treating a cancerous orprecancerous state having or being induced by vitamin D receptors, on anindividual in need of such treatment, comprising administering to suchindividual, a thus effective amount of the pharmaceutical composition asdefined by claim
 6. 27. A regime or regimen for treating alopecia, on anindividual in need of such treatment, comprising administering to suchindividual, a thus effective amount of the pharmaceutical composition asdefined by claim
 6. 28. A regime or regimen for treating an immunecomplaint, condition or affliction, on an individual in need of suchtreatment, comprising administering to such individual, a thus effectiveamount of the pharmaceutical composition as defined by claim
 6. 29. Aregime or regimen for treating an endocrine complaint, condition oraffliction, on or in an individual in need of such treatment, comprisingadministering to such individual, a thus effective amount of thepharmaceutical composition as defined by claim
 6. 30. A regime orregimen for treating abnormal management of intracellular calcium, or acalcium metabolism pathology, on or in an individual in need of suchtreatment, comprising administering to such individual, a thus effectiveamount of the pharmaceutical composition as defined by claim
 6. 31. Aregime or regimen for treating a vitamin D deficiency, or a disorder ofthe homeostasis of minerals in the plasma and the bones, on or in anindividual in need of such treatment, comprising administering to suchindividual, a thus effective amount of the pharmaceutical composition asdefined by claim
 6. 32. A regime or regimen for treating a complaint,condition or affliction of the cardiovascular system, in an individualin need of such treatment, comprising administering to such individual,a thus effective amount of the pharmaceutical composition as defined byclaim
 6. 33. A regime or regimen for treating non-insulin-dependantdiabetes, in an individual in need of such treatment, comprisingadministering to such individual, a thus effective amount of thepharmaceutical composition as defined by claim 6.